About 100,000,000 people have the Type II diabetes mellitus all over the world, which is characterized in hyperglycemia caused by excessive hepatic glucose production and peripheral insulin resistance. The hyperglycemia is considered to be a major risk factor for forming the diabetic complication, and be possibly directly relevant to insulin secretion impairment in the later stage of Type II diabetes mellitus. Therefore, it can be expected that the normalization of blood glucose in the patients having the Type II diabetes mellitus can improve the effect of insulin. The currently known anti-diabetic drugs such as sulfonylureas, thiazolidinediones, dimethyl biguanides, and insulins have potential side effects, and therefore there is a need to develop a new and safe anti-diabetic drug that can be orally administrated effectively.
In kidney, glucose can filter freely through renal glomerulus (about 180 g/d) but nearly transport actively at proximal convoluted tubule to be reabsorbed. Among others, two sodium-glucose transporters, i.e. SGLT1 and SGLT2, have an important effect on the glucose reabsorption, in particular SGLT2. SGLT2 specifically expresses the transmembrane protein only at the S1 section of proximal tubule. One of its major physiological functions is to absorb the glucose in the blood flowing through the renal tubule, which comprises 90% of the reabsorption. SGLT2 transports at a ratio of 1:1 sodium-glucose. The SGLT-2 inhibitor can inhibit the absorption of blood glucose in the renal tubule so that a great amount of glucose excretes through the urine. SGLT1 mainly expresses in the distal convoluted tubule, which comprises 10% of the reabsorption. SGLT1 transports at a ratio of 2:1 sodium-glucose. In addition, SGLT1 is also found in the intestinal tract and other tissues. These transporters exert their functions via Na+/ATPase pump and transport to the blood via the glucose transporter-2 (GLUT2). This indicates that the most potential drug target is the SGLT2 transporter, because its absolute re-absorption for glucose in one hand and its merely expression in kidney in the other hand. In the study on the urine glucose from the nephrosis of the familial form, the feasibility of this route has been verified. The urine glucose from the nephrosis of the familial form is mainly manifested as non-quantitative urine glucose (about 10-120 g/d), but the patient has a good general condition and has no chronic negative effect adverse for the health to be found. This benign urine glucose is mainly caused by the genic mutation of the SGLT-2 transporter, which indicates that the selective pharmacological inhibition to SGLT-2 will possibly not produce an adverse effect except for the induction of urine glucose. However, the inhibition SGLT-1 will cause the glucose-galactose malabsorption syndrome, which may result in the dehydration.
By action on SGLT-2 transporter to inhibit the reabsorption of the kidney glucose to treat the high blood glucose, a new route for treating the diabetes mellitus is provided. Although this route cannot directly act on the pathophysiology of Type II diabetes mellitus, however the reduction of blood glucose by increasing the excretion of glucose in kidney can cause the deficiency in the net energy to promote losing the body weight and indirectly improve the obesity conditions. It is found in the study that these drugs can be used in combination of the existing drug for reducing the blood glucose or the insulin, and have a lower risk of the low blood glucose and a potential effect of losing the weight. The safety and effectiveness in the chronic clinical experiment will eventually determine whether the SGLT-2 inhibitor can have a place in the pharmaceutical treatment of the Type II diabetes mellitus.
Among others, the patent literatures such as WO 0127128 and US 2005209166 disclose a series of compounds as SGLT-2 inhibitor.